Guanine nucleotide-binding proteins (GTP-binding proteins) participate in a wide range of regulatory functions including metabolism, growth, differentiation, signal transduction, cytoskeletal organization, and intracellular vesicle transport and secretion. These proteins control a diverse sets of regulatory pathways in response to hormones, growth factors, neuromodulators, or other signaling molecules. When these molecules bind to transmembrane receptors, signals are propagated to effector molecules by intracellular signal transducing proteins. Many of these signal transducing proteins are members of GTP-binding proteins.
The low molecular weight (LMW) GTP-binding proteins are a class of small proteins which consist of single polypeptides of 21-30 kDa. These proteins regulate cell growth, cell cycle control, protein secretion, and intracellular vesicle interaction. In particular, the LMW GTP-binding proteins activate cellular proteins by transducing mitogenic signals involved in various cell functions in response to extracellular signals from receptors (Tavitian, A. (1995) C. R. Seances Soc. Biol. Fil. 189:7-12). During this process, the hydrolysis of GTP acts as an energy source as well as an on-off switch for the GTPase activity of the LMW GTP-binding proteins.
The LMW GTP-binding proteins have been grouped into four subfamilies: Ras, Rho, Ran, and Rab. Specifically, Ras genes are essential in the control of cell proliferation and mutant Ras genes have been associated with cancer; Rho proteins control signal transduction in the process of linking receptors of growth factors to actin polymerization which is necessary for cell division; Rab proteins control the translocation of vesicles to and from membranes for protein localization, protein processing, and secretion; and Ran proteins are located in cell nucleus and have a key role in nuclear protein import, control of DNA synthesis, and cell-cycle progression.
Four sequence regions, termed motifs I-IV, are conserved in the LMW GTP-binding proteins. Motif I is the most variable region and has the signature, GXXXXGK. The lysine residue is essential in interacting with the .beta.- and .lambda.-phosphates of GTP. Motif II, III, and IV are highly conserved, with DTAGQE, NKXD, EXSAK/L as their respective signatures. These motifs regulate the binding of .lambda.-phosphate, GTP, and the guanine base of GTP, respectively.
Several Rho GTP-binding proteins have been identified in plasma membrane and cytoplasm. These include Rho A, B and C, rhoG, rac 1 and 2, G25K-A and B, and TC10 (Hall, A. et al. (1993) Philos. Trans. R. Soc. Lond. (Biol.) 340: 267-271). All Rho proteins have a Cys-aliphatic residue-aliphatic residue-X (CAAX) box for the binding of a prenyl group and either a palmitoylation site or a basic amino acid-rich region, suggesting their role in membrane-associated functions. Rho A, B, and C are shown to have about 30% identity with the Ras proteins (Chardin, P. (1988) Nucleic Acids Res. 16:2717). The expression of Rho C is shown to be associated with murine macrophage activation by silica (Segade, F. et al. (1995) J. Immunol. 154: 2384-2392). During cell adhesion, the Rho proteins are essential for triggering focal complex assembly and integrin-dependent signal transduction (Hotchin, N. A. and Hall, A. (1995) J. Cell Biol. 131: 1857-1865).
The discovery of a new human Rho protein and the polynucleotides which encode it satisfies a need in the art by providing new compositions which are useful in diagnosis, prevention, and treatment of disorders associated with proliferation and inflammation.